LEO Pharma Announces That Picato® (ingenol mebutate) gel has Been Approved by US FDA for Once-Daily, 2 or 3 day Treatment of Actinic Keratoses

COPENHAGEN, Denmark, January 26, 2012 /PRNewswire/ --

LEO Pharma today announced that Picato^® (ingenol mebutate) gel (0.015%, 0.05%) has been approved by the US Food and Drug Administration (FDA) as a treatment for actinic keratoses (AK) on the face, scalp, trunk and extremities. Picato^® gel is a once-daily, field-directed topical treatment for AK, a potential precursor to non-melanoma skin cancer caused by cumulative sun exposure. Treatment with Picato^® gel is completed over two consecutive days for AK on the trunk and extremities and over three consecutive days on the face and scalp.

Actinic keratoses often appear as red, scaly skin lesions mainly seen on sun-exposed areas such as the face, the scalp and extremities, where they can occur as a singlelesion or multiple lesionsacross an entire field.^[1] The lesions are typically caused by cumulative UV exposure and the condition affects an increasing number of people, especially in Europe, the US and Australia.^[2] According to the Skin Cancer Foundation, they affect about 58 million Americans and are the most common form of pre-cancer.^[3]

Actinic keratoses are precursors to skin cancer and can progress to squamous cell carcinoma (SCC), a type of non-melanoma skin cancer which is the second most common type of skin cancer.^[4] The risk of progression to SCC increases with the number of lesions present^[5] and it is impossible to predict which lesions will develop into skin cancer. A study has shown that around 65 percent of cases of squamous cell carcinoma may begin as actinic keratoses.^[6]

Picato^® (ingenol mebutate) gel is a field-directed topical therapy which enables treatment of an area affected by actinic keratoses. It is available in two different concentrations: for treatment of the face and scalp, the gel is applied at a concentration of 0.015% once daily, completing treatment in three consecutive days, whereas for treatment of the body, the gel is applied once daily for two consecutive days at a concentration of 0.05%.The FDA approval is based on data from four phase III studies in over 1000 patients treated with ingenol mebutate (n=503) or placebo (n=502) showing that ingenol mebutate applied once-daily for two or three consecutive days is significantly more effective than placebo at clearing actinic keratoses. ^[7-10]The most common Local Skin Reactions (LSRs) included erythema, flaking/scaling, crusting and swelling. Other AEs occurring in ≥ 2 percent of subjects treated with Picato^® in the phase III clinical trials included pain, pruritus and infection at the site of application, as well as periorbital edema and headache when applied on face or scalp.

Commenting on today's announcement, Mark Lebwohl, M.D, Professor and Chair, Department of Dermatology, Mount Sinai Medical Center in New York, said,"Since there is no way to predict which actinic keratoses will advance to skin cancer, early detection and treatment of lesions are critical. What makes this new therapy particularly exciting is the two or three day course of treatment."

Gitte P. Aabo, Chief Executive Officer of LEO Pharma, said, "Actinic keratoses affect millions of people, but many are not aware that they have the condition or that in some cases it can lead to skin cancer.Picato^® gel requires just two or three consecutive days of treatment, compared to several weeks or months for existing topical therapies. We believe this shorter duration of treatment will be well received by both patients and clinicians. The approval of Picato^® gel is another important step in LEO Pharma's goal of becoming one of the world's leading dermatology companies."

LEO Pharma expects Picato^® to be available to US physicians in March 2012.

About Picato^® gel

Picato^® is a topical gel containing ingenol mebutate, derived from the Euphorbia peplus plant. The dried plant passes through an extraction, purification and crystallization process over approximately five months to become an active pharmaceutical ingredient (API). For the production of Picato^® gel, a carefully selected cultivar of Euphorbia peplusplant is grown by farmers for LEO Pharma in Queensland, Australia, to ensure consistency in performance.

Picato^® gel is a topical, field-directed therapy which is self-administered by the patient on to the affected areas of the skin once a day for two or three consecutive days.Picato^® has two concentrations and two application regimens to follow dependent upon the location of the AK: Picato^® gel can be applied over two consecutive days for treatment of AK on the trunk and extremities and over three consecutive days on the face and scalp.

Clinical trial history

To date, 18 clinical trials have been completed for the use of Picato^®, from phase I trials through to pivotal phase III trials. In phase III clinical trials, 60^[8] to 68^[9] percent of patients with actinic keratosis on the face and scalp saw 75 percent or greater reduction of existing AKs (versus 7 to 8 percent with placebo, p<0.001). Picato^® also demonstrated efficacy in treating the trunk and extremities with 44^[11] to 55^[8] percent of patients experiencing 75 or more percent reduction (versus 7 percent reduction for placebo, p<0.001). Patients treated with Picato^® saw 37^[8]-47^[9] percent complete clearance of lesions on the face and scalp, and 28^[10]-42^[7] percent on the trunk and extremities.

The most common LSRs included erythema, flaking/scaling, crusting and swelling. LSRs peaked within the first week and generally resolved within two weeks in the majority of patients treated on the face and scalp, and within four weeks for patients treated on the trunk and extremities.Other AEs occurring in ≥ 2 percent of subjects treated with Picato^® in the phase III clinical trials included pain, pruritus and infection at the site of application, as well as periorbital edema and headache when applied on face or scalp.

Important safety information

For topical use only; not for oral, ophthalmic, or intravaginal use. Eye disorders, including severe eye pain, eyelid edema, eyelid ptosis, periorbital edema can occur after exposure. Patients should wash hands well after applying Picato^®gel, and avoid transfer of the drug to the periocular area during and after application.Severe skin reactions in the treated area, including erythema, crusting, swelling, vesiculation/pustulation, and erosion/ulceration, can occur after application. Administration of Picato^®gel is not recommended until the skin is healed from any previous drug or surgical treatment. The most common adverse reactions observed in clinical trials (≥2 %) are local skin reactions, application site pain, application site pruritus, application site irritation, application site infection,periorbital edema, nasopharyngitis and headache. There are no adequate and well-controlled studies of Picato^®gel in pregnant women. Picato^® gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The safety and effectiveness of Picato^®gel for actinic keratosis in patients less than 18 years of age have not been established.

Please see full prescribing information available at http://www.leo-pharma.us.

About actinic keratoses

Actinic keratoses are skin lesions, the majority of which are caused by cumulative UV exposure (usually from the sun) in fair-skinned people.Lesions are often red, scaly and may initially be mistaken for a rash or other skin irritation, but do not improve over time. The number of patients with actinic keratoses is both large and rapidly growing, especially in Europe, the US and Australia, with the American Academy of Dermatology estimating that 60% of predisposed persons older than 40 have at least one actinic keratosis lesion. ^[11-12]People at high risk are often over the age of 40 and tend to have fair skin and a history of sun exposure.^[11]

The most important risk factor for the development of actinic keratoses is cumulative UV-radiation, which is reflected in the geographical distribution of prevalence in the susceptible population. Similarly, an increase in vacational and recreational sun exposure during the past decade has led to the increased prevalence.^[13] AKs are more common in males, and individuals with a fair skin type are predisposed.Additional risk factors that have been identified include advanced age and immunodeficiency. Immuncompromised patients show a significant increase in AKs, with a 65 to 250 fold higher risk for AKs and invasive SCC.^[14]

Actinic keratoses are considered to be the earliest stage in the development of non-melanoma skin cancer,with the potential to progress to squamous cell carcinoma, a non-melanoma cancer which is the second most common type of skin cancer.^[15] The average person developing multiple actinic keratoses, also known as field cancerization, has an up to 10% risk of one or more of these lesions developing into squamous cell cancer within ten years.^[16] The risk of progression to SCC increases with the number of lesions present^[5] and it is impossible to predict which lesions will develop into skin cancer. A studyhas shown that around 65 percent of squamous cell carcinoma cases may begin as actinic keratoses.^[6] and patients with the condition are six times more likely to develop any type of skin cancer than people without it.^[17]

About LEO Pharma

Founded in 1908, LEO Pharma is an independent, research-based pharmaceutical company. LEO Pharma develops, manufactures and markets pharmaceutical drugs to dermatologic and thrombotic patients in more than 100 countries globally. The company has its own sales forces in 61 countries and employs more than 4,600 employees worldwide. LEO Pharma is headquartered in Denmark and is wholly owned by the LEO Foundation. For more information about LEO Pharma, visit http://www.leo-pharma.com.

References

1.    Stockfleth E, Kerl H. Guidelines for the management of actinic keratoses. Eur J Dermatol 2006;16(6):599-606.

2.    Bickers DR, Lim HW, Margolis D, Weinstock MA, Goodman C, Faulkner E, et al. The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J Am Acad Dermatol 2006;55(3):490-500.

3.    Skin Cancer Facts, Skin Cancer Foundation.

4.    Lansbury L, Leonardi-Bee J, Perkins W, Goodacre T, Tweed JA, Bath-Hextall FJ. Interventions for non-metastatic squamous cell carcinoma of the skin. Cochrane Database Syst Rev 2010(4):CD007869.

5.    Green A, Battistutta D. Incidence and determinants of skin cancer in a high-risk Australian population. Int J Cancer 1990;46(3):356-61.

6.    Feldman SR, Fleischer AB, Jr. Progression of actinic keratosis to squamous cell carcinoma revisited: clinical and treatment implications. Cutis 2011;87(4):201-7.

7.    Anderson L, Melgaard A, Xu Z. Multicenter, randomized, parallel-group, double-blind, vehicle-controlled, phase 3 study to evaluate the efficacy and safety of PEP005 (ingenol mebutate) gel, 0.05% in patients with actinic keratoses on non-head locations (Study PEP005-028). Poster presented at: 22nd World Congress of Dermatology 2011 May 24-29 Seoul, Korea. Poster P2180.

8.    Berman B, Melgaard A, Larsson T. Multicenter, randomized, parallel-group, double-blind, vehicle-controlled phase 3 study of the efficacy and safety of PEP005 (ingenol mebutate) gel, 0.015% in patients with actinic keratoses on the head (face or scalp) (Study PEP005-016). Poster presented at: 22nd World Congress of Dermatology 2011 May 24-29 Seoul, Korea. Poster P2179.

9.    Lebwohl M, Melgaard A, Xu Z. Randomized, parallel-group, double-blind, vehicle-controlled, multicenter phase 3 study of the efficacy and safety of PEP005 (ingenol mebutate) gel, 0.015% in patients with actinic keratoses on the head (Study PEP005-025). Poster presented at: 22nd World Congress of Dermatology 2011 May 24-29 Seoul, Korea. Poster P2181.

10.    Swanson N, Melgaard A, Larsson T. Multicenter, randomized, parallel-group, double-blind, vehicle-controlled phase 3 study to evaluate the efficacy and safety of PEP005 (ingenol mebutate) gel, 0.05% in patients with actinic keratoses on non-head locations (Study PEP005-014). . Poster presented at: 22nd World Congress of Dermatology 2011 May 24-29 Seoul, Korea. Poster P2182.

11.    Drake LA, Ceilley RI, Cornelison RL, Dobes WL, Dorner W, Goltz RW, et al. Guidelines of care for actinic keratoses. Committee on Guidelines of Care. J Am Acad Dermatol 1995;32(1):95-8.

12.    Ko CJ. Actinic keratosis: facts and controversies. Clin Dermatol 2010;28(3):249-53.

13.    Ulrich M, Drecoll U, Stockfleth E. Emerging drugs for actinic keratosis. Expert Opin Emerg Drugs 2010;15(4):545-55.

14.    Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med 2003;348(17):1681-91.

15.    Mittelbronn MA, Mullins DL, Ramos-Caro FA, Flowers FP. Frequency of pre-existing actinic keratosis in cutaneous squamous cell carcinoma. Int J Dermatol 1998;37(9):677-81.

16.    Berman B, Amini S, Valins W, Block S. Pharmacotherapy of actinic keratosis. Expert Opin Pharmacother 2009;10(18):3015-31.

17.    Chen GJ, Feldman SR, Williford PM, Hester EJ, Kiang SH, Gill I, et al. Clinical diagnosis of actinic keratosis identifies an elderly population at high risk of developing skin cancer. Dermatol Surg 2005;31(1):43-7.

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SOURCE LEO Pharma